Evidence for sodium valproate toxicity in mitochondrial diseases: a systematic analysis

Background We aimed to determine whether sodium valproate (VPA) should be contraindicated in all mitochondrial diseases, due to known VPA-induced severe hepatotoxicity in some mitochondrial diseases. Methods We systematically reviewed the published literature for mitochondrial DNA (mtDNA) and common nuclear genotypes of mitochondrial diseases using PubMed, Ovid Embase, Ovid Medline and MitoPhen databases. We extracted patient-level data from peer-reviewed articles, published until July 2022, using the Human Phenotype Ontology to manually code clinical presentations for 156 patients with genetic diagnoses from 90 publications. Results There were no fatal adverse drug reactions (ADRs) in the mtDNA disease group (35 patients), and only 1 out of 54 patients with a non-POLG mitochondrial disease developed acute liver failure. There were fatal outcomes in 53/102 (52%) POLG VPA-exposed patients who all harboured recessive mutations. Conclusions Our findings confirm the high risk of severe ADRs in any patient with recessive POLG variants irrespective of the phenotype, and therefore recommend that VPA is contraindicated in this group. However, there was limited evidence of toxicity to support a similar recommendation in other genotypes of mitochondrial diseases.

MitoPhen-Expanded dataset: The search strategy used to compile this dataset is as per the MitoPhen database [3] -where PubMed is searched for 'gene' and 'mitochondrial disease*' or 'clinical*'.Title and abstract reviews were performed to exclude ar3cles which did not contain pa3ent-specific informa3on by co-author KS.POLG dataset: Two data collectors (co-authors NE and AL) have addi3onally gathered data on treatments documented.The pathogenicity of POLG variants was checked using American College of Medical Gene3cs guidelines [4], the 'Human DNA Polymerase Gamma Muta3on Database' [5], and through expert consensus between co-authors KS and RH.The MitoPhen-Expanded dataset was searched for any probands with human phenotype ontology (HPO) terms rela3ng to headache, migraine, and seizures.Addi3onal family members diagnosed with mitochondrial disease were included if sodium valproate (VPA) treatment was men3oned.
Nuclear genotypes associated with mitochondrial complexes I-V deficiency: PanelApp [2] was used to iden3fy 'green' genes in these categories, and the search strategy is as above.Co-author CG collected pa3ent-specific data including on treatments.Note: there were no men3ons of sodium valproate in the MitoPhen-Expanded OPA1 and TWNK datasets, therefore we have not included these datasets in this paper.

Data extrac.on and review
Author TR screened the ar3cles and collected the data.The data collected from ar3cles documen3ng VPA use in pa3ents with mitochondrial diseases included sex of pa3ent, age at onset of symptoms, HPO terms (manually extracted), age at VPA use, age at adverse drug reac3on (ADR), type of ADR, and whether the ADR was ul3mately fatal.Author PFC performed a secondary review of included ar3cles to ensure correct interpreta3on of data.

Risk of bias assessment summary
Author TR screened ar3cles using the Joanna Briggs Ins3tute case report cri3cal appraisal tool [6].Ar3cles very infrequently reported dosages and frequency of administering VPA and did not report blood monitoring of VPA levels.Addi3onal confounders such as other an3seizure medica3ons were used in case reports, especially in the POLG disease datasets, which contributes to difficulty in ascertaining the true effect of VPA in ADR severity.However, the clinical presen3ng features and effects of suspected VPA toxicity were consistently reported across all groups.Therefore, the study was not suitable for a metaanalysis, but results could be synthesised using a phenotype-driven approach, and overall rate of ADRs could be commented on.

Figure
Figure S1 Phenotypic clustering across 156 pa5ents with mitochondrial diseases and VPA exposure.A: Heatmap shows hierarchical clustering of phenotype similarity scoring, causa5ve genes are displayed on the right, and the categories of gene are shown at the boHom -indica5ng clustering of non-POLG disease in cluster 5. Cluster numbers are coloured and shown at the top of the dendrogram.The row-side colours represent documented adverse drug reac5ons (orange) or not (green).B: Survival curves for each phenotypic cluster are presented, pairwise comparisons conducted using the Log-Rank test showed a significant difference in survival between Cluster 1 and Cluster 5 against other clusters (excluding Cluster 3) (p<0.05).Confidence intervals displayed at a 95% confidence level.C: Table highlights the frequent HPO terms seen in each cluster (with five or more pa5ents documented to have the term), terms found in all clusters are shown at the boHom.

Figure
Figure S2 Frequency bar charts of top 20 human phenotype ontology (HPO) terms.A: Top 20 terms in 102 pa5ents with POLG disease and VPA exposure-status epilep5cus seen in >25%.B: Top 20 terms in 284 pa5ents with POLG disease and no VPA exposure-status epilep5cus seen in 50%.C: Top 20 terms in 54 pa5ents with non-POLG disease and VPA exposure, status epilep5cus not within top 20 terms.
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Search strategy for mtDNA disease
Search terms used were the same as for the POLG disease dataset above but each of the 89 pathogenic mtDNA variants within MitoPhen were reviewed.

Search strategy for non-POLG nuclear genes
Search terms used were the same as for the POLG disease dataset above but each of the PanelApp genes listed above, were reviewed.

Table S1
Summary of data for published pa5ents with mtDNA diseases and VPA exposure.BMJ Publishing Group Limited (BMJ) disclaims all liability and responsibility arising from any reliance Supplemental material placed on this supplemental material which has been supplied by the author(s)